The effects of ryanodine on left ventricular (LV) function and hemodynamics were studied in 16 conscious dogs, chronically instrumented for measurements of LV pressures and dimensions. Systemic infusion of ryanodine (0.5 - 4 fg/kg i.v.) resulted in a dose-dependent depression of cardiac contraction. For example, ryanodine, 4.0 g/kg i.v., decreased LV fractional shortening by 30.5q4.1%, LV dP/dt by 41.5q4.0% and Vcfc by 37.8q4.1%, while increasing the isovolumic relaxation time constant, tau, from 23.1q1.4 to 34.1q3.6 msec without a major effect on preload or afterload. Ryanodine also depressed (p<0.05) the plateau phase of the mechanical restitution and postextrasystolic potentiation responses, indicating a direct effect on excitation-contraction coupling. The heart rate dependent positive staircase ("Treppe") was significantly enhanced (p<0.05) after ryanodine infusion, i.e. LV dP/dt rose by 43.1q4.7% with an increase in heart rate from 150 to 240 beats/min in the presence of ryanodine 4 fg/kg, but by only 7.5q2.1% without ryanodine. The more pronounced "Treppe" in the conscious dog under the condition of impaired SR calcium release caused by ryanodine, supports the concept that the classical Bowditch "Treppe"reflects either a state of myocardial depression due to alteration in SR calcium handling, or enhanced availability of trans-sarcolemmal Ca2+ influx. This finding may help to understand the discrepancy in the importance of the "Treppe" between conscious animals and more isolated preparations.